Electrotransport system having flexible connector means

ABSTRACT

A device (10) for the electrically assisted delivery of a therapeutic agent is described. The device (10) has rigid zones or regions (12, 14) which are physically connected by a flexible means (16) such as a web. The flexible means (16) permits the rigid zones (12, 14) to move independently with respect to each other while remaining physically connected or coupled. In a preferred embodiment, the rigid zones are physically and electronically coupled by the flexible means. In another embodiment, the device (500) comprises one or more rigid zones, the skin side of the rigid zone having a radius of curvature (520) which approximates that of the body site to which the device (500) is to be attached. A method of increasing the body surface conformability of an electrotransport device (50, 150, 170) is described. The method involves the step of intentionally placing rigid subcomponents (58, 36, 37) of the device in physically separate zones (52, 54; 152, 154, 156, 158; 172, 174, 176, 178) within the device. The rigid zones (52, 54; 152, 154, 156, 158; 172, 174, 176, 178) are separate and are coupled by flexible connector means (56, 62; 160, 162). In this manner, a conformable mosaic of rigid zones which comprises the device is created.

This is a continuation-in-part of U.S. patent application Ser. No.07/999,206 filed Dec. 31, 1992 now abandoned.

TECHNICAL FIELD

This invention generally concerns apparatuses for the electricallyassisted delivery of a therapeutic agent. Such apparatuses are referredto broadly herein as electrotransport devices.

More specifically, this invention relates to electrotransport drugdelivery devices in which active species or drugs are directly orindirectly delivered through the skin of a patient by application ofelectromotive force. Yet more specifically, this invention relates toelectrotransport devices having physically coupled, substantially rigidzones or regions wherein the means of coupling permits the zones orregions to be planar or non-planar and thereby to conform to complex,curved and non-planar surfaces. Yet even more specifically, thisinvention relates to electrotransport devices, such as iontophoresisdevices, having physically and electrically coupled rigid zones orregions which are maintained in intimate contact with a patient's skinso as to deliver, transdermally, drug or therapeutic agent.

BACKGROUND ART

The present invention concerns apparatuses for transdermal delivery ortransport of therapeutic agents, typically through iontophoresis. Hereinthe terms "electrotransport", "iontophoresis", and "iontophoretic" areused to refer to methods and apparatus for transdermal delivery into thebody of therapeutic agent, whether charged or uncharged, by means of anapplied electromotive force to an agent-containing reservoir. Theparticular therapeutic agent to be delivered may be completely charged(ie, 100% ionized), completely uncharged, or partly charged and partlyuncharged. The therapeutic agent or species may be delivered byelectromigration, electroosmosis, electroporation or a combination ofthese. Electroosmosis has also been referred to as electrohydrokinesis,electro-convection, and electrically-induced osmosis. In general,electroosmosis of a therapeutic species into a tissue results from themigration of solvent, in which the species is contained, as a result ofthe application of electromotive force across the therapeutic speciesreservoir-tissue interface.

As used herein, the terms "iontophoresis" and "iontophoretic" refer to(1) the delivery of charged drugs or agents by electromigration, (2) thedelivery of uncharged drugs or agents by the process of electroosmosis,(3) the delivery of charged drugs or agents by the combined processes ofelectromigration and electroosmosis, (4) the delivery of a mixture ofcharged and uncharged drugs or agents by the combined processes ofelectromigration and electroosmosis, and/or (5) the delivery of chargedor uncharged drug(s) or agent(s) by the combined processes ofelectromigration, electroosmosis, and electroporation.

Iontophoretic devices for delivering ionized drugs through the skin havebeen known since the early 1900's. Deutsch U.S. Pat. No. 410,009 (1934)describes an iontophoretic device which overcame one of thedisadvantages of such early devices, namely that the patient needed tobe immobilized near a source of electric current. The Deutsch device waspowered by a galvanic cell formed from the electrodes and the materialcontaining the drug to be transdermally delivered. The galvanic cellproduced the current necessary for iontophoretically delivering thedrug. This device allowed the patient to move around duringiontophoretic drug delivery and thus imposed substantially lessinterference with the patient's daily activities.

In presently known iontophoresis devices, at least two electrodes areused. Both of these electrodes are disposed so as to be in intimateelectrical contact with some portion of the skin of the body. Oneelectrode, called the active or donor electrode, is the electrode fromwhich the ionic substance, agent, medicament, drug precursor or drug isdelivered into the body via the skin by iontophoresis. The otherelectrode, called the counter or return electrode, serves to close theelectrical circuit through the body. In conjunction with the patient'sskin contacted by the electrodes, the circuit is completed by connectionof the electrodes to a source of electrical energy, eg, a battery; andusually to circuitry capable of controlling current passing through thedevice. For example, if the ionic substance to be driven into the bodyis positively charged, then the positive electrode (the anode) will bethe active electrode and the negative electrode (the cathode) will serveto complete the circuit. If the ionic substance to be delivered isnegatively charged, then the cathodic electrode will be the activeelectrode and the anodic electrode will be the counter electrode. Insome instances, the drug may be formulated such that in one formulationthe drug ions are positively charged and in a second formulation thedrug ions are negatively charged. In such situations, the positivelycharged drug ions may be delivered from the anode and/or the negativelycharged drug ions may be delivered from the cathode. Hence, drugdelivery may occur from one or both electrodes and may occursimultaneously as well as sequentially.

Furthermore, existing iontophoresis devices generally require areservoir or source of the beneficial agent or drug, preferably anionized or ionizable species (or a precursor of such species) which isto be iontophoretically delivered or introduced into the body. Such drugreservoirs are connected to the anode or the cathode of an iontophoresisdevice to provide a fixed or renewable source of one or more desiredspecies or agents.

Perhaps the most common use of iontophoresis today is in diagnosingcystic fibrosis by delivering pilocarpine transdermally.Iontophoretically delivered pilocarpine stimulates sweat production, thesweat is collected, and is analyzed for its chloride ion content.Chloride ion concentration in excess of certain limits suggests thepossible presence of the disease.

Electrotransport devices generally contain an electronic circuit whichcontrols the current output of the device. In more recent years, thesize of electrotransport devices has been reduced to a point where thedevices can be mounted and worn on the skin. In order to protect,adequately, the electronic circuitry in such skin-mounted devices andfor a variety of other reasons, these devices have generally utilized asubstantially rigid container or assembly. See for example Lattin et al,U.S. Pat. No. 4,406,658 (FIGS. 2 and 3) and Lattin et al, U.S. Pat. No.4,457,748 (FIGS. 1, 3 and 4). While these rigid devices were acceptablein those applications (eg, cystic fibrosis diagnosis) which required thepatient to wear the device for only a short period of time, ie, on theorder of 30 minutes or less, these devices have been found to besomewhat uncomfortable in those applications where the patient must wearthe device for periods longer than an hour. Particularly in applicationswhere the patient must wear the device for an extended period of time(eg, days, weeks or months) comfort is a significant issue.

In response to these difficulties, the advantages of developing aflexible electrotransport delivery device were recognized. For example,Ariura et al, U.S. Pat. No. 4,474,570, discloses one example of aflexible iontophoresis device. This device utilizes electrode assembliescomprised of a current distributing conductive layer, a drug orelectrolyte salt-containing gel layer and a thin backing layer, alllaminated together. The Ariura device utilizes minimal electroniccircuitry, specifically only a single button cell battery which isconnected though a flexible lead wire to an electrode assembly. In orderto make the device completely flexible, Ariura utilizes thin "sheet"batteries which have a thickness of only about 0.5 to 2 mm. Because theAriura et al device is completely flexible, it is able to conform tomany irregular body surfaces and can be worn comfortably for longerperiods of time. While flexible iontophoretic delivery devices, such asthat disclosed by Ariura et al represent a significant advantage overrigid devices, in terms of comfort for the wearer, they present otherdisadvantages. For example, the Ariura et al device is very limited interms of the electronic circuitry which may be utilized in the deviceand yet still retain its flexible characteristics. Furthermore, thereare many iontophoretic drug delivery applications which the currentrequirements are too high for the single small battery disclosed in theAriura et al device. If multiple batteries are placed in the Ariura etal device, the device becomes substantially nonflexible and therebyloses its comfort advantage.

In addition to batteries, electrotransport delivery devices may haveother components which are themselves relatively rigid and inflexible(ie, one or more electrical components) or which require a relativelyrigid housing in order to adequately protect the component duringshipping and handling of the device. For example, "dry" electrotransportdelivery devices which are hydrated immediately before use sometimescarry on-board water pouches. In order to adequately safeguard againstpremature hydration caused by inadvertent rupture of the on-board waterpouches, it may be necessary to provide structural rigidity to thedevice at least in the vicinity of the water pouches. Other devicecomponents, eg, delicate electronics, may require at least portions ofthe electrotransport device to be relatively rigid to provideprotection, electrical continuity or other function.

Unfortunately, devices having rigid regions generally do not conformwell to the body site to which the device is attached, particularly whenthe means of attachment is a releasable contact adhesive. This can causean electrotransport system to peel away from the body site, or toalternatively cause internal layers of the device itself to detach ordelaminate and thereby fail. This invention allows an electrotransportdrug delivery device having rigid regions to conform to the body surface(eg, to skin) to which it is adhesively held with a reduced tendency topeel away.

U.S. Pat. No. 4,752,285 to Petelenz discloses a wrist-disposediontophoresis device held in place by a bracelet comprising aniontophoresis apparatus including a remote electrode. The iontophoresisapparatus and electrode of Petelenz U.S. Pat. No. '285 are connected bywires to a separate current source.

The present invention overcomes the problems encountered in the priorart and is not suggested or disclosed in the references alone or incombination.

DISCLOSURE OF THE INVENTION

Briefly, in one aspect, the present invention is an assembly or devicefor delivering an agent by electrotransport through a body surface. Adevice of this invention has at least two rigid regions which areadapted to be maintained in ion-transmitting relationship with the bodysurface at spaced apart locations, and which are held in their spacedapart locations preferably by means of biocompatible adhesive. Despitesubstantial rigidity, at least a drug delivery component of the assemblyof this invention is maintained in intimate, drug-transmitting relationwith the body surface. A device of this invention further includes aflexible connector means which physically connects the rigid regions butwhich permits the rigid regions to move with respect to each otherduring agent electrotransport without loss of intimate contact with thesurface of the patient's body. Specific embodiments of flexibleconnector means of this invention include hinges and flexible polymericwebs.

In a preferred practice of this invention, the flexible connector meansboth (1) physically connects or couples the rigid zones to one another;and (2) electronically connects a component in one of the rigid zones toa component in the other rigid zone. Generally, this means that aflexible electronic conductor comprises a part of the flexible connectormeans. More preferably, the flexible connector means physically connectsthe donor and counter electrodes of the electrotransport deliverydevice. Most preferably, the flexible connector means is extendable,thereby allowing the zones (eg, the electrodes) to be placed at closelyadjacent locations or more spaced apart locations on the patient's body.

In a preferred practice, the rigid components or zones of the assemblyof this invention are held in intimate, ion-transmitting relation to aportion of a patient's body by means of a biocompatible adhesive.

In yet another preferred practice, a device of this invention has aplurality of rigid zones and a plurality of flexible connector meansphysically or physically and electronically coupling the rigid zones.

In a further preferred practice of this invention, the rigid regions arecontoured to the body surface to which they are applied.

Preferably, the rigid regions have a flexural rigidity, EI, greater thanabout 1.5×10⁻³ kg-m² /rad and the flexible connector means has aflexural rigidity of less than about 0.75×10⁻³ kg-m² /rad. Morepreferably, the rigid regions have a flexural rigidity of greater thanabout 5.0×10⁻³ kg-m² /rad and the flexible connector means has aflexural rigidity of less than about 0.45×10⁻³ kg-m² /rad. Mostpreferably, the rigid regions have a flexural rigidity of greater thanabout 15×10⁻³ kg-m² /rad and the flexible connector means has a flexuralrigidity of less than about 0.15×10⁻³ kg-m² /rad. In addition, thedifference between the flexural rigidity of a rigid region and theflexural rigidity of the flexible connector means (ΔEI) is preferablygreater than about 0.3×10⁻³ kg-m² /rad, more preferably greater thanabout 1.5×10⁻³ kg-m² /rad, and most preferably greater than about5.0×10⁻³ kg-m² /rad.

The flexural rigidity of a rigid zone and/or a flexible connector meansis measured in accordance with the test method described in connectionwith FIG. 12, hereinafter.

BRIEF DESCRIPTION OF THE DRAWINGS

The present invention may be better understood with reference to thedetailed description below and the attached drawings in which likenumerals are used to refer to like features throughout and in which:

FIG. 1 is a perspective view of one embodiment of the present invention;

FIG. 1A is an enlarged side view of the flexible connector means 16shown in FIG. 1;

FIG. 1B is a side view of an alternate connector means 16' which can beused in place of flexible connector means 16 shown in FIG. 1A.

FIG. 2 is an exploded view of a second embodiment of the presentinvention similar to that of FIG. 1

FIG. 2A is an enlarged partial section side view of its flexibleconnector means 16" shown in FIG. 2.

FIG. 3 is a perspective view of another embodiment of the presentinvention;

FIG. 4 is an exploded view of the components of the device shown in FIG.3;

FIG. 5 is an exploded, perspective view of another embodiment of thisinvention;

FIG. 6 is a perspective, partial phantom view of another embodiment ofthe present invention;

FIG. 7 is a perspective, partial phantom view of the embodiment of theinvention shown in FIG. 6 but rotated approximately 45° from theorientation shown in FIG. 6;

FIG. 8 is a top view of yet another embodiment of the present invention;

FIG. 9 is another top view of the device shown in FIG. 8 in which therigid components 204 and 206 have been physically separated;

FIG. 10 and FIG. 11 are further embodiments of the present invention;

FIG. 12 is a side view of an apparatus for measuring the flexibilityand/or rigidity of an electrotransport device or any component thereof;

FIG. 13 is yet a further embodiment of the present invention;

FIG. 14 is a perspective view of a further embodiment of the presentinvention;

FIG. 15 is a perspective view of the device shown in FIG. 14 with theelectrode assemblies in an extended configuration;

FIG. 16 is a top view of the device shown in FIG. 14;

FIG. 17 is a sectional view of the device shown in FIGS. 14-16, takenalong line XVII--XVII in FIG. 16; and

FIG. 18 is a sectional view of the device shown in FIGS. 14-17 takenalong line XVIII--XVIII in FIG. 16.

MODES FOR CARRYING OUT THE INVENTION

Thus there is shown, in FIG. 1, a perspective view of anelectrotransport device or assembly 10 of this invention.Electrotransport device 10 comprises two rigid (as defined herein)housings or subassemblies 12, 14 connected by flexible connector means16. Housings 12 and 14 each comprise rigid zones or region, which rigidzones or regions are physically connected to one another by flexibleconnector means 16. Device 10 includes a flexible, biocompatible or skincompatible adhesive sheet 18 which preferably extends beyond the outerperimeter of housings 12, 14. By making the area of adhesive sheet 18larger than the area of housings 12, 14 there is greater area of contactbetween sheet 18 and a patient's skin resulting in more secureattachment of the device 10 thereto. The extension of the peripheraledges of flexible sheets 18 beyond the peripheral edges of rigidhousings 12, 14 also permits a more gentle transition between thepatient's skin and rigid housings 12, 14, thereby making device 10 morecomfortable to wear.

The rigid housings 12, 14 may contain, for example, electrical circuitcomponents which are coupled through eg, flexible hinge 16. The circuitcomponents are mounted (and protected) in the two rigid housings 12, 14.These housings are preferably comprised of a substantiallythermoplastic, rigid material. The housings 12, 14, themselves, aresubstantially incapable of conforming to the contour of the underlyingskin surface and, but for hinge 16, would eventually cause theunderlying adhesive sheet 18, (which contains a typical skin contactadhesive) either to peel away from the skin, or pull on the skin andthereby cause discomfort for the wearer as a result of normal bodymovement.

In FIG. 1A there is shown a detail of the flexible connector 16 whichphysically (and preferably) electronically couples or connects rigidhousings 12, 14. Connector 16 comprises a base 17 on which adhesive 18is located. Base 17 and adhesive 18 have a zone, line, or means of flexwhich in this example is simply a "necked down" region or portion 25 ofthe support member. The necked down segment 25 is more flexible than therest of the support structure. Alternatively a cross-sectioned "V"segment could be used in place of the "necked down" region shown toprovide the increased flexibility or flex zone, region or line. Segment25 permits rigid zones 12, 14 to move independently with respect to eachother while maintaining their physical proximity. Base 17 may furthercomprise flexible electronic coupler means. This embodiment of theinvention is discussed below. Base 17 may or may not contain flexiblecircuitry depending upon the rest of the device construction. In theembodiment shown base 17 contains flexible electrical connector orcircuitry (not shown).

Another example of a flexible connector means which can be used flexiblyto connect rigid housings 12, 14 is hinge 16' shown in FIG. 1B. Hinge16' is formed by inserting flexible fin 17 into recess 19 in housing 12.Fin 17 is slidably received in recess 19, allowing fin 17 to slide inand out of recess 19 as housings 12, 14 are flexed about hinge 16'.Thin, flexible zone 31 provides a region or area which permits housings12, 14 to bend or flex with respect to each other. Those skilled in theflexible hinge art will readily appreciate that any number of hingedesigns may be used in place of the specific designs illustrated inFIGS. 1A, 1B and 2A.

The terms "rigid" and "flexible" are used to describe not only housings12, 14, and hinge 16, respectively, but are also used extensivelyelsewhere herein. The term "rigid" when used in describing a portion orzone of an electrotransport system means that the portion or zone hassufficient stiffness so as to be incapable of adhering to a body surface(eg, to skin) of a patient using a biocompatible and pharmaceuticallyacceptable contact adhesive without injury to the body surface oridentifiable patient discomfort, throughout the normal range of bodymotion. In other words, a "rigid" zone of an electrotransport system isprone to peel from the skin, or alternatively to undergo delamination ofadjacent layers within the rigid zone of the system, thereby interferingwith the desired agent or drug delivery protocol.

The term "flexible" when used to describe the flexible means whichconnects the rigid zones of an electrotransport system means havingsufficient flexibility so as to enable the "rigid" portions or zones ofthe system to be capable of adhering to the body surface, by means of abiocompatible, pharmaceutically acceptable contact adhesive withoutinjury to the body surface or identifiable patient discomfort,throughout the normal range of body motion and for the time period inwhich drug or agent is to be delivered.

Those skilled in the art may readily determine the flexibility orrigidity of a particular component or zone in an electrotransport systemby using the following test method. Although any number of stress-straintesting apparatus may be used to determine flexural rigidity, onepreferred apparatus is an Instron stress-strain testing machine ModelNo. 1122 which may be used interchangeably with a number of differenttension load cells. A preferred load cell for testing the flexibleconnector means of the present invention is the Instron 2000 gm tensionload cell Model No. A30-38(A). A preferred tension load cell formeasuring the flexural rigidity of the rigid zones according to thepresent invention is an Instron 500 kg tension load cell. A tension loadcell used to determine the parameters used in this application isdescribed below with reference to FIG. 12.

FIG. 2 shows an exploded view of an electrotransport delivery device 10'of this invention in which the rigid housing 12' and 14' (which containthe battery(ies) and any associated electronic circuitry) are shownseparated from a flexible sheet 20 which is secured to the underside ofhousings 12', 14' during use of device. Sheet 20 may be attached to theunderside of housings 12' and 14' by conventional means, eg, anadhesive, rivets, or snap connectors (not shown in the figure) orcombination of these attachment means. The skin contacting undersurfaceof sheet 20 may itself be tacky, (eg, tacky polyisobutylene) or may becoated with an appropriate biocompatible contact adhesive (eg, asilicone adhesive). In this manner, device 10' may be adhered to apatient's skin by flexible, biocompatible adhesive sheet 20. Sheet 20 issubstantially the same size as the outer profile of housings 12', 14'and thus does not extend beyond the outer periphery of housings 12',14'. Sheet 20 is preferably comprised of a material which issubstantially impermeable to the passage of ions therethrough, eg, ahydrophobic adhesive material. Provided within the sheet 20 are wells 21and 22 which contain a donor reservoir 23 containing the agent to bedelivered and a counter reservoir 24 containing a biocompatibleelectrolyte salt. The reservoirs 23 and 24 are preferably comprised of ahydrophilic polymer (eg, a gel) matrix loaded with either the beneficialagent or the biocompatible electrolyte salt, respectively. Thus, each ofreservoirs 23 and 24 contain an agent or salt, and preferably anionizable agent or salt, which is suitable for delivery into the body.Sheet 20 is adapted to be secured to the bottom of housings 12' and 14'in a manner which electrically connects the reservoirs 23 and 24 withappropriate current conducting members within housings 12', 14'respectively.

Optionally, the upper or skin distal portion of device 10' (ie,housings, 12', 14' and all of the electronic components containedtherein) is releasably attached to sheet 20, enabling the user to removesheet 20, after the agent contained in reservoir 23 has been depleted,and replace it with a new sheet 20. In this manner, the upper portion ofdevice 10' is reusable and the lower or skin proximal portion of device10' (ie sheet 20) is adapted to be discarded after a single use and thenreplaced.

A flexible hinge 16" provides a flexible coupling between the two rigidzones comprising housings 12' and 14'. Components in housing 12' can beelectronically connected to components in housing 14' across theflexible coupling of this invention eg, when the flexible connectormeans includes a flexible, conductive electronic circuit or componentthereof. This is discussed in greater detail below.

One preferred example of a flexible coupler means or hinge 16 comprisesa flexible plastic material, or what is sometimes referred to in thisart as a "living hinge". A side view of such a hinge 16" is shown inpartial section detail in FIG. 2A. The hinge 16" of FIG. 2A is acompound hinge comprised of a polymeric web 33 having three fold lines11, 13 and 15. Fold lines 11, 13 and 15 are generally perpendicular tothe plane of FIG. 2A. Adhesive 18 and base 17 also are shown in FIG. 2A.Base 17 has a relatively thinner flex zone or line 35 which, as shown,is a "V". Polymeric web 33 and flex line 35 permit rigid segments 12',14' to bend with respect to each other. Web 33 and flex line 35 arealigned so that they can be flexed substantially in unison.

FIG. 3 shows an alternative, perspective embodiment of the invention.Electrotransport delivery device 30 includes two rigid zones comprisedof rigid housings 32 and 34. Rigid housings 32, 34 contain batteries 37(shown in phantom) and other electronic circuitry (not shown). Housing32 optionally contains an indicator 44 and a bolus switch 46. Bolusswitch 46, when activated by the patient or a medical professional,provides a higher level of electrical current for a predetermined orpredeterminable period of time. This produces a correspondingly higherdrug delivery over the predetermined time, providing a bolus of drug tothe patient. Indicator 44 (an LED) provides an indication of whether thebolus is activated.

Housings 32, 34 are flexibly coupled by hinge 36 which flexes aroundimaginary axis 38. Thus in this embodiment, like devices 10 and 10', theflexible means flexes about an axis or line of flex. Housings 32, 34bend or flex about hinge 36, from the substantially planar positionshown to a non-planar position shown in phantom by reference numeral 40.The rigid, substantially planar housings 32, 34 are attached to anadhesive sheet 42 which is used to adhere device 30 to a body surface.Because of hinge 36, the rigid planar housings can be flexed aboutimaginary axis 38 in order to comfortably conform to a generally curvedor contoured portion of a patient's body to which device 30 is attachedvia adhesive sheet 42.

FIG. 4 is an exploded view of a device 50 of the invention. As shown,device 50 includes two substantially rigid (eg, molded polypropylene)housings 52, 54 coupled by a flexible, uniaxial hinge 56. Rigid housing52 houses one or more electronic circuit components 58 (eg, capacitors,transistors, an oscillators, or a pulse generator, etc), while rigidhousing 54 houses batteries 37. The rigidity of both these case segmentsis dictated by functional concerns, eg, protection of internalcomponents, and the rigidity of the internal components themselves.

As shown, circuit component 58 and batteries 37 are disposed on aflexible printed circuit board 60. Flexible printed circuit board 60typically has a plurality of circuit traces (not shown in FIG. 4)interconnecting batteries 37 and circuit component(s) 58. Flexibleprinted circuit board 60 has at least one flexible hinge or axis of flex62 which cooperates with cover hinge 56 to provide two substantiallyparallel and closely adjacent axes or lines of flexibility whichtogether define a flexible connector means comprising a plane or zone offlexibility or flex.

Printed circuit board 60 may be coupled or connected to rigid housingmembers 52, 54 by any appropriate means eg, an adhesive, snapconnectors, rivets, etc. Printed circuit board 60 is coupled to sheet 20containing reservoirs 23 and 24 by conventional means as describedearlier with regard to FIG. 2.

FIG. 5 is an exploded view of another device 100 according to thepresent invention. Device 100 has a rigid, two-halved upper cover orhousing 102. Upper housing 102 comprises two substantially planar,rigid, halves 104, 106 coupled or connected by a flexible compound hinge108. As with the device 50 of FIG. 4, device 100 has a bolus switch 110which may be activated by the patient or a medical professional afterthe device is positioned on the patient's body. Housing 102 also has aperipheral lip which improves the level of comfort experienced by thepatient wearing the device. Generally speaking a peripheral lip musthave sufficient width to comfortably hold the device against thepatient's skin during the full range of body motion without excessivelydistorting the skin surface to which it adheres so as to cause pain ordiscomfort.

Device 100 further includes a lower housing 114, and a flexible circuit116 which sits on lower housing or base component 114. Lower housing 114comprises two substantially rigid sections, 119, 121 connected by aflexible hinge 123. Flex circuit 116 includes a necked segment 117 whichelectronically couples its two halves. Positioned over flexible circuit116 is a battery spacer 120 which holds the batteries (not shown) inposition over the battery terminal contacts 118 of flexible circuit 116.Lower housing 114 has a flexible peripheral lip or edge 125 whichextends beyond or outside the profile of the device defined by upperhousing 102. Such a lip is a preferred construction because it enhancesthe ability of the device to be held to a patient's skin during drugdelivery (eg, by an adhesive) without distorting the patient's skin soas to cause discomfort. Generally speaking, the wide lip must be moreflexible than the rigid segments to which it is attached in order toachieve this comfort and conformability objective.

Also of importance in FIG. 5 is the substantial coincidence or planarityof hinge 108 in upper housing 102, necked segment 117 of circuit 116 andthe flexible hinge 123 in lower housing 114. These three elementsprovide flexible physical and electrical coupling between thesubstantially rigid halves of the device shown in FIG. 5. These elementsin combination illustrate a planar flex means or flexible connectormeans of this invention.

It is well within the design choice of those skilled in this art todetermine which of the various assembly components shall be hinged sothat physical connection is achieved. For example, the two halves 104,106 of upper housings 102 may comprise separate pieces if the lowerhousing 114 and the lower hinge 123 are sufficiently strong so as toretain the physical proximity of the rigid sections of the assembly.Alternatively, upper housing 102 may be comprised of a single hingedpiece (eg, halves 104, 106 physically coupled by hinge 108) and lowerhousing 114 may comprise physically separate sections 119, 121. Thesedesign variations are well within the skill of one familiar with thisart.

FIG. 6 illustrates an embodiment of the present invention in which theelectrotransport device 150 has multiple rigid modules 152, 154, 156,158 and a plurality of flexible connector means or regions 160, 162.Device 150 therefore has two separate and distinct flexible regions 160,162. The axes of flex of regions 160 and 162 are substantiallyperpendicular. An array of independent, rigid, but physically connectedmodules 152, 154, 156, 158 connected by flexible regions 160, 162 isgenerated.

Of particular note from FIG. 6 is the curved shape of the skincontacting surfaces of electrotransport device 150. As can be seen,flexible region 160 divides device 150 into two rigid segments 151, 153.Each of the segments 151, 153 has a curved skin contacting surface, 155,157, respectively. The curved (as opposed to planar) surfaces 155, 157are preferred because many likely device application sites on the bodyare curved and/or have roughly a cylindrical shape. For example, thearms legs, torso, neck, and fingers all have substantially curved orcylindrical surfaces. A rigid segment 151, 153 having a surface 155, 157with a radius of cylindrical curvature in the range of 40 to 60 mm ispreferred for conforming to the arms of human adults having differentbody sizes, shapes and physiques. A rigid segment 151, 153 having asurface 155, 157 in the range of about 12 to 18 mm radius of cylindricalcurvature is preferred for conforming to the fingers and toes of humanadults. A range of about 60 to 90 mm radius of cylindrical curvature ispreferred for surfaces conforming to the legs of human adults. A rigidsegment 151, 153 having a surface 155, 157 with greater than about a 125mm radius of cylindrical curvature is preferred for conforming to thetorsos of human adults. The radius of a curved, rigid segment isselected substantially to match the smallest body site (eg, torso) sizesencountered in the patient population group to which the device is to beapplied. In this manner, the largest possible area of skin contact willresult. The resulting enhanced conformity of the device 150 to the bodysurface, particularly along the edges of the modules 153 and 155, willreduce the likelihood that a module will snag (eg, on the patient'sclothing) and peel off the skin during wear. By virtue of thecylindrical, concave underside of surfaces 155 and 157, forces whichtend to bias the edges of modules 151 and 153 away from the skin contactsurface, which forces are typically observed during the attachment of aflat, single-piece rigid device on the skin of a patient, can be greatlyreduced.

By utilization of an array of smaller rigid modules 152, 154, 156 and158, disposed on a suitably flexible web or sheet (eg, sheet 19 shown inFIGS. 2, 4 and 5), the individual modules can be quite thick and alsoquite rigid and yet the entire device 150 remains flexible (ie, moreable to conform to the natural shape of a body surface). This is dueprimarily to the presence of flexible regions 160 and 162. Thisobservation is particularly applicable if the rigid modules areadequately separated (eg, by flexible regions 160 and 162) on a flexibleconnecting "web" or film and the skin contacting surfaces of the modulesare curved, angled or radiussed, as depicted in FIG. 6. Generallyspeaking, it is necessary for any bridge between individual modules bethin and substantially coplanar, otherwise a structure will be producedthat will be extremely stiff and non-conformable.

FIG. 7 shows a further embodiment of this invention. Device 170 iscomprised of multiple rigid modules 172, 174, 176 and 178 which arephysically coupled by means of a flexible web 180. This arrangementprovides two flexible regions having substantially perpendicular axes offlex. The rigid modules 172, 174, 176 and 178 are also electronicallycoupled to one another (at 182, 184, 186 and 188) by flexible electroniccircuits. In this embodiment the flexible coupling means includes theportion of web 180 between the rigid segments 172, 174, 176, and 178 andcircuit couplings 182, 184, 186, and 188 and the underlying sheet (eg,sheet 19) which is not shown in FIG. 7. Like device 150 the individualrigid segments of device 170 are curved or are concave on their skinfacing surfaces (eg, their underside surfaces) to enhance skin contactas described above. Web 180 is adhesive on its bottom side to attachsheet 19 (not shown) thereto. The skin contacting surface of sheet 19 iseither itself tacky or is coated with a biocompatible skin contactadhesive in order to hold the device 170 in drug transmitting relationto the patient's skin.

Electrotransport devices 150 and 170 illustrated in FIGS. 6 and 7,respectively, demonstrate a further important embodiment of the presentinvention. The level of comfort experienced by the wearer of a rigidelectrotransport system of a certain size may be increased by dividingthe overall size of the device into a number of smaller subunits (eg,subunits such as the rigid modules 152, 154, 156 and 158 shown in FIG. 6or the rigid modules 172, 174, 176 and 178), each of which subunits mayitself be rigid as defined herein. However, rather than a single largerigid device, the smaller rigid subunits are interconnected by way offlexible connector means as defined herein. Preferably, the individualrigid subunits have lateral dimensions (ie, lengths and widths asmeasured roughly parallel to the body surface to which theelectrotransport system is applied) in the range of 10-35 mm, morepreferably in the range of 15-25 mm. Most preferably, the individualrigid subunits have lateral dimensions within these ranges and also haveskin contacting surfaces with radii of cylindrical curvature asdescribed above.

FIGS. 8 and 9 are top views of another embodiment 200 of the presentinvention. Device 200 has an "accordion-type" flexible connector means202, which couples, both physically and electronically, rigid devicecomponents 204, 206. As is shown in FIGS. 8 and 9, flexible connectormeans 202 has a non-extended configuration shown in FIG. 8 and anextended configuration shown in FIG. 9. Thus, device 200 may be placedon a patient's body surface (eg, skin) with webs 208 placed in closelyadjacent locations on the body surface. Alternatively, by extending theflexible connector means 202, the webs 208 may be placed in more spacedapart locations on the patient's body surface. As is clearly shown inFIG. 9, the flexible connector means 202 is serpentine shaped. Thus, inthe non-extended configuration (FIG. 8), the connector means 202 has aplurality of overlapping portions. These over lapping portions becomenon-overlapping as the flexible connector means 202 is extended into themore extended configuration shown in FIG. 9. Device components 204, 206are adhered to the patient's body surface by means of the web 208 whichhas a biocompatible adhesive on its skin contacting side (not shown).Various web profiles may be employed depending upon the body applicationsite and artistic considerations.

FIGS. 14 to 18 illustrate another embodiment of this invention.Electrotransport device 70 comprises an electronic controller 71 and asingle-use/disposable electrode unit 72. Electrode unit 72 comprises adonor electrode assembly 74 and a counter electrode assembly 73. Unlikeother embodiments of the invention described herein, donor electrodeassembly may be either rigid, as that term is used herein, or non-rigid.The controller 71 is adapted to releaseably engage electrode unit 72 bymeans of electrically conductive snap connectors 84, 85 as best shown inFIG. 17. Once the controller 71 engages snap connectors 84, 85, thecombined assembly of controller 71 and counter electrode 73 comprises arigid zone. In accordance with the present invention, electrodeassemblies 73 and 74 are physically connected to one another by aflexible means 75. Flexible means 75 has a non-extended configuration(shown in FIG. 14) and an extended configuration (shown in FIG. 15).Thus, device 70 is manufactured with the flexible means 75 having thenon-extended serpentine configuration shown in FIG. 14. Thisconfiguration allows device 70 to be used on a patient with electrodeassemblies 73 and 74 positioned closely adjacent to one another on thepatient's body. However, if it is desired to place the electrodeassemblies 73 and 74 at more distantly spaced locations on the patient'sbody, the flexible means 75 may be extended as shown in FIG. 15.

The device 70 with the extendible flexible means 75 is particularlyuseful in electrotransport devices which are adapted to deliver a druglocally (ie, to a specific body site) as opposed to systemic drugdelivery. Examples of locally acting drugs include delivery of localanesthetics for inducing localized anesthesia, delivery ofanti-inflammatory agents (eg, NSAID's) for treatment of jointinflammation, delivery of antifungal agents for treating nail fungus,delivery of wart removing agents (eg, salicylic acid) to warts, deliveryof anti-tumor drugs to treat skin tumors, delivery of anti-spasmodicagents to treat localized muscle spasms, and delivery of maleerection-inducing agents (eg, prostaglandin E1 or papavarine) directlyinto the penis. One particularly useful application of device 70 is fordelivery of local anesthetic agents in order to induce local anesthesiaprior to minor surgical procedures, wart removals, mole removals,venipuncture procedures, and in giving hypodermic injections inpediatric applications. For example, if device 70 is used to deliver alocal anesthetic agent, such as lidocaine, procaine, bupivacaine,mepivacaine, etidocaine, dibucaine, chloroprocaine, xylocaine,prilocaine, benzocaine, tetracaine, combinations thereof, and mixturesthereof with vasoconstricting agents such as epinephrine andnaphazoline, or the like, in order to remove a mole, and the mole islocated on the patient's face, it is desirable to attach the counterelectrode assembly 73 at a body surface location other than on thepatient's face, for example on the upper arm or shoulder. In order toaccomplish this, the flexible means 75 is extended by pulling apart theelectrode assemblies 73, 74 and a more distant spacing of the electrodesis easily achieved.

In addition to physically connecting the electrode assemblies 73 and 74,the flexible means 75 has an electrically conductive circuit trace whichelectrically connects the donor electrode assembly 74 to the controller71. FIG. 18 shows a sectional view of flexible means 75 taken alonglines XVIII--XVIII of FIG. 16. Flexible means 75 comprises amultilaminate structure including a layer 76 of closed-cell polyolefinfoam (eg, polyethylene foam having a thickness of 0.8 mm (1/32 inch) andsold by 3M, St. Paul, Minn.) which is coated on one side with apressure-sensitive (eg, acrylate) adhesive. In addition to closed-cellpolyolefin foams, layer 76 can also be composed of fabric (woven ornon-woven), or an elastomer (eg, a rubber). On the adhesive coated faceof layer 76 is laminated a ink-printable sheet 77, such as Mylar 200Dpolyester, having a thickness of 0.05 mm (2 mils) and sold by E. I.DuPont DeNemours & Company, Wilmington Del. In addition to polyesters,sheet 77 can also be composed of polyolefins such as polyethylene, orpolyvinylchloride. A continuous trace of electrically conductive ink 78is printed on the polyester sheet 77. Suitable inks include silver,silver chloride and carbon based conductive inks. A particularlypreferred conductive ink is sold by Acheson Colloids Co. of Port Huron,Mich. and designated by Model No. SS24381. After printing conductive inktrace 78 on polyester sheet 77, the sheet 77 and trace 78 are coatedwith an insulating coating 79, providing insulation between theconductive ink trace 78 and the patient. Preferred insulative coatingmaterials are UV curable dielectric coatings sold by Acheson ColloidsCo. under the tradenames ML-25094 and ML-25208.

As best shown in FIG. 17, the donor electrode assembly 74 is comprisedof a foam layer 81 having a centrally positioned cavity holding a donorreservoir 82. Reservoir 82 preferably comprises a gel holding a solutionof the drug or other agent to be delivered by device 70. Similarly,counter electrode assembly 73 is comprised of a foam layer 83 having acentrally positioned cavity holding a counter reservoir 86. Preferably,reservoir 86 contains a solution of a biocompatible electrolyte.

The disposable electrode unit 72 is adapted to be physically andelectrically connected to controller 71 by means of snap connectors 84and 85. Snap connectors 84, 85 may be constructed of metal (eg,stainless steel, nickel-coated brass or silver-coated brass) or metalcoated polymers (eg, silver-coated ABS). Snap connector 85 electricallyconnects the counter electrode assembly 73 to the controller 71 whereassnap connector 84 electrically connects, through conductive ink trace78, the donor electrode assembly 74 to the controller 71.

Controller 71 contains a pair of serially connected batteries 90 whichprovide the electrical power for device 70. Controller 71 includes acircuit board 91 having electrical components for controlling the timingand level of the applied current. Circuit board 91 includes an LED 92which may be viewed through the opening 93 in the controller housing.The LED may be illuminated, for example, when the device is inoperation.

FIGS. 10 and 11 illustrate two further embodiments of this invention.Devices 300 and 302 each have a flexible but non-stretchable connectormeans 304, 306, respectively, which electronically and physically couplerigid components 308, 310 and 312, 314, respectively. The rigidcomponents may contain batteries or electronic circuit components withno particular significance being attached to which rigid components areincluded within the respective rigid assemblies. The connector means ofFIG. 10 is a plurality of fairly rigid rubber connectors having partiallateral slices projecting inwardly from the edge while in FIG. 11 theconnector means is a rubber coated band.

FIG. 13 illustrates a single rigid electrotransport assembly 500 of theinvention. A single rigid assembly similar to that of FIG. 13 isdescribed in detail in U.S. Pat. No. 5,158,537, the pertinent portionsof which are incorporated by reference herein. Assembly 500 compriseselectrode assemblies 502, 504, separated by insulator 506. Electrodeassemblies 502, 504 have drug and electrolyte reservoirs 508, 510 andcurrent distribution members 514, 514', respectively. An electroniccircuit, which generates and/or controls the electric current applied byelectrotranport assembly 500, is electrically connected to currentdistribution members 514 and 514' and is illustrated schematically inFIG. 13 as layer 512. An optional water-proof backing layer covers layer512. Agent/ion-conducting adhesive layers 515 are used to hold device500 to a patient's skin.

Electrotransport assembly 500 has a skin or body proximal side 516 andan exterior or body distal side 518. Body proximal side 516 has a curvedconfiguration (indicated by arrows 520) which enhances the ability ofthe rigid assembly to adhere to the site of drug delivery, eg an arm,leg or torso, as will be understood. The radius of curvature of bodyproximal side 516 is adjusted to substantially match the radius ofcurvature of the body site on which the device is to be attached.

The above-described invention provides a great deal of device designlatitude. For example, by utilization of detachable couplers orconnectors in conjunction with the flexible connector means, individualdevice components, or even entire subassemblies may be made detachable.For example, a substantially rigid battery subassembly could be detachedfrom the rest of the electrotransport assembly and replaced when thebattery is discharged. Alternatively, a discharged drug source could bedetached and replaced (for replenishment) or a different drug (or adifferent drug concentration) may be substituted.

This invention relates primarily to electrotransport devices havinginherently rigid structures or zones. In one practice, zones of anelectrotransport apparatus are joined by specialized flexural orflexible membrane structures which allow the rigid elements to beoriented in different planes without peeling away from the patient'sskin. This permits the electrotransport device structure as a whole to"bend" or "flex" to conform to cylindrical or even free form geometry,thus maintaining an intimate adhesive contact with the skin.

The invention consists of, in the case of an electrotransport system, amulti-layered (eg, electrode/circuit/drug reservoir/salt reservoir,wicking layer, skin contact, optionally ion-conducting adhesive, and/orelectron-conducting adhesive) structure which, because of its novelconfiguration, remains flexible and conformable to preferred mountingsites on the human body. There are other applications for thisstructural configuration which will be obvious to those skilled in thisfield: Skin-mounted infusion devices, skin-mounted passive transdermaldevices, diagnostic devices and monitoring devices that should beattached to the skin. The "other applications" have two things(requirements) in common which make them benefit from this invention:(1) the need to be intimately attached to a significant area of skin and(2) the essentially, rigid nature of their structure, which are notcompatible requirements.

In this invention, the largest, non-reducible (not able to be brokeninto sub-modules) element of the system that is structurally rigid andcannot itself be reconfigured to curve-match to the mounting site, canbe taken as the standard module size in an array of rigid elementsflexibly connected into a conformable, essentially planar structure. Inthe example of this invention applied to the design of anelectrotransport system, the largest rigid element is generally the"button cell" battery. As shown in the figures, the basic module isdrawn around the battery, closely enveloping it but presenting a 50millimeter cylindrical section surface on one side for attachment to thebody on sites as small as the 90th percentile female arm and larger.Other modules of identical size may contain other rigid componentssmaller than the battery. In the example in FIG. 6, four modules arejoined to form the flexible array.

FIG. 12 illustrates a test fixture for testing the flexural rigidity ofan electrotransport system 10 on the Instron stress-strain testingmachine Model No. 1122. The tension load cell 401 of the Instronstress-strain testing machine is attached to device 10 by means of aclamp 403 and a cable 405, each of which exhibit minimal (ie, <1%)tensile elasticity (eg, clamp 403 and cable 405 are composed of a metalsuch as stainless steel). As shown in FIG. 12 the test apparatus is setup to test the flexural rigidity of flexible hinge 16 which is locatedbetween rigid housing 12 and 14. In this set-up, clamp 403 is clampedonto rigid housing 12 while rigid housing 12 is at rest in asubstantially horizontal orientation. Another clamp 407 holds housing 14substantially along its width and length right up to the flexible hinge16. Those skilled in the art will appreciate that the clamp 407 must becustom designed to test a particular system 10. For example, clamp 407has an opening 408 in which the rigid housing 14 is held. The angle ofthe axis of opening 408 is determined by the shape of device 10 whendevice 10 is in a non-flexed (ie, rest) condition. Those skilled in theart will also appreciate that clamp 407 will have an opening 408 with anaxis at varying angles to the horizontal depending upon the shape of theparticular device being tested. For example, if the electrotransportdevice had a substantially planer configuration (rather than theslightly bent or V-shaped configuration of device 10) in a non-flexedrest condition, then the axis of opening 408 would be substantiallyhorizontal.

Clamp 407 is securely fastened by conventional means to the moveablecross-head of the Instron stress-strain testing machine. The length (1)of cable 405 is preferably long enough to satisfy the followingrelation:

    I/L≦10

wherein L is the moment arm (see FIG. 12) and I is the distance from thetest device to the load cell 401, in order to minimize the effect of thehorizontal movement of the clamped end of housing 12 as device 10 flexesaround hinge 16.

The flexural rigidity of hinge 16 is measured according to the followingprocedure. First, the cross-head 409 is moved downwardly to take allslack out of cable 405. Housing 12 should be substantially horizontal atthe point where testing is begun. The cross-head 409 is moved downwardlyat a cross-head speed of 50 mm/min. causing the rigid housings 12, 14 tobend at an angle θ from the rest position, while the Instron testingmachine plots the force-deflection curve. The flexural rigidity, whichis the product of the Young's modulus (E) and the moment of inertia (I),is then calculated from the loads and deflection angles measured by theInstron stress-strain testing machine using the following equation:

    EI=WL.sup.2 /2θ

where:

E=Young's modulus (or modulus of elasticity);

I=moment of inertia;

W=the applied load;

L=the moment arm; and

θ=the angle of deflection

Those skilled in the art will readily appreciate how the apparatusillustrated in FIG. 12 may be modified in order to test the flexuralrigidity on one of the rigid housing 12, 14. For example. in order totest the flexural rigidity of rigid housing 14, the housing 12 may beremoved (eg, by cutting the system along flexible hinge 16). The rigidhousing 14 is then placed within a horizontal opening 408 within clamp407. A sufficient portion of rigid housing 14 must extend out from clamp407 in order to enable clamp 403 to be attached hereto.

The terms "agent" or "drug" are used extensively herein. As used herein,the expressions "agent" and "drug" are used interchangeably and areintended to have their broadest interpretation as any therapeuticallyactive substance which is delivered to a living organism to produce adesired, usually beneficial, effect. In general, this includestherapeutic agents in all of the major therapeutic areas including, butnot limited to, anti-infectives such as antibiotics and antiviralagents, analgesics and analgesic combinations, anesthetics, anorexics,antiarthritics, antiasthmatic agents, anticonvulsants, anti-depressants,antidiabetic agents, antidiarrheals, antihistamines, anti-inflammatoryagents, antimigraine preparations, antimotion sickness preparations,antinauseants, antineoplastics, antiparkinsonism drugs, antipruritics,antipsychotics, antipyretics, antispasmodics, including gastrointestinaland urinary antispasmodics, anticholinergics, antiulceratives,sympathomimetrics, xanthine derivatives, cardiovascular preparationsincluding calcium channel blockers, beta agonists, beta-blockers,antiarrythmics, antihypertensives, ACE inhibitors, benzodiazepineantagonists, diuretics, vasodilators, including general, coronary,peripheral and cerebral, central nervous system stimulants, cough andcold preparations, decongestants, diagnostics, hormones, hypnotics,immunosuppressives, muscle relaxants, parasympatholytics,parasympathomimetrics, prostaglandins, proteins, peptides, polypeptidesand other macromolecules, psychostimulants, sedatives and tranquilizers.

The present invention can be used to iontophoretically deliver thefollowing drugs: α-2b interferon, alfentanyl, amphotericin B,angiopeptin, atenolol, baclofen, beclomethasone, betamethasone,bisphosphonates, bromocriptine, buserelin, buspirone, buprenorphine,calcitonin, ciclopirox olamine, copper, cromolyn sodium, desmopressin,diclofenac diflorasone, diltiazem, dobutamine, dopamine agonists,dopamine agonists, doxazosin, droperidol, enalapril, fentanyl,encainide, flumazenil, G-CSF, GM-CSF, M-CSF, GHRF, GHRH, gonadorelin,goserelin, granisetron, haloperidol, hydrocortisone, indomethacininsulin, insulinotropin, interleukin, isosorbide dinitrate, ketoprofen,,ketorolac, leuprolide, LHRH, lidocaine, lisinopril, LMW heparin,melatonin, methotrexate, metoclopramide, miconazole, midazolam,nafarelin, nicardipine, nifedipine, NMDA antagonists, octreotide,ondansetron, oxybutynin, PGE₁, piroxicam, pramipexole, prazosin,prednisolone, prostaglandins, ranitidine, ritodrine, scopolamine,seglitide, sufentanil, terbutaline, testosterone, tetracaine,tropisetron, vapreotide, vasopressin, verapamil, warfarin, zacopride,zinc, zotasetron.

This invention is also believed to be useful in the iontophoreticdelivery of peptides, polypeptides and other macromolecules typicallyhaving a molecular weight of at least about 300 daltons, and typically amolecular weight in the range of about 300 to 40,000 daltons. Specificexamples of peptides and proteins in this size range include, withoutlimitation, LHRH, LHRH analogs such as buserelin, gonadorelin,napharelin and leuprolide, GHRH, GHRF, insulin, insulinotropin, heparin,calcitonin, octreotide, endorphin, TRH, NT-36 (chemical name: N═(s)-4-oxo-2-azetidinyl!carbonyl!-L-histidyl-L-prolinamide), liprecin,pituitary hormones (eg, HGH, HMG, HCG, desmopressin acetate, etc,),follicle luteoids, αANF, growth factors such as growth factor releasingfactor (GFRF), βMSH, TGF-β, somatostatin, atrial natriuretic peptide,bradykinin, somatotropin, platelet-derived growth factor, asparaginase,bleomycin sulfate, chymopapain, cholecystokinin, chorionic gonadotropin,corticotropin (ACTH), epidermal growth factor, erythropoietin,epoprostenol (platelet aggregation inhibitor), follicle stimulatinghormone, glucagon, hirudin and hirudin analogs such as hirulog,hyaluronidase, interferon, insulin-like growth factors, interleukin-2,menotropins (urofollitropin (FSH) and LH), oxytocin, streptokinase,tissue plasminogen activator, urokinase, vasopressin, desmospressin,ACTH analogs, ANP, ANP clearance inhibitors, angiotensin II antagonists,antidiuretic hormone agonists, antidiuretic hormone antagonists,bradykinin antagonists, CD4, ceredase, CSF's, enkephalins, FABfragments, IgE peptide suppressors, IGF-1, neuropeptide Y, neurotrophicfactors, opiate peptides, parathyroid hormone and agonists, parathyroidhormone antagonists, prostaglandin antagonists, pentigetide, protein C,protein S, ramoplanin, renin inhibitors, thymosin alpha-1,thrombolytics, TNF, vaccines, vasopressin antagonist analogs, alpha-1anti-trypsin (recombinant).

Generally speaking, it is most preferable to use a water soluble form ofthe drug or agent to be delivered. Drug or agent precursors, ie, specieswhich generate the selected species by physical or chemical processessuch as ionization, dissociation, or dissolution, are within thedefinition of "agent" or "drug" herein. "Drug" or "agent" is to beunderstood to include charged and uncharged species as described above.

Numerous characteristics and advantages of the invention covered by thisdocument have been set forth in the foregoing description. It will beunderstood, however, that this disclosure is, in many respects, onlyillustrative. Changes may be made in details, particularly in matters ofshape, size, and arrangement of parts without exceeding the scope of theinvention. The invention's scope is, of course, defined in the languagein which the appended claims are expressed.

We claim:
 1. A device for delivering an agent by electrotransportthrough a body surface, the device having a source of electrical powerelectrically connected to a pair of electrode assemblies, one of thepair of electrode assemblies having a reservoir for containing the agentto be delivered, the device comprising at least two regions which areplaced against the body surface at spaced apart locations and which areheld in intimate contact with said body surface, at least one of the tworegions being rigid and comprising the power source and an electrodeassembly, the regions being physically connected to one another by aconnector, the connector having a folded non-extended configuration andan unfolded extended configuration, whereby the regions may be placed onthe body surface at: (i) a first set of locations when the connector isin the folded non-extended configuration, or (ii) a second set oflocations less proximate that the first set of locations when theconnector is in the extended unfolded configuration.
 2. The device ofclaim 1, wherein the first set of locations is more closely spaced thanthe second set of locations.
 3. The device of claim 1, wherein theconnector is accordion shaped or serpentine shaped.
 4. The device ofclaim 3, wherein the connector is comprised of a plurality ofoverlapping portions when in the non-extended configuration, at leastsome of the overlapping portions becoming non-overlapping when theconnector is in the extended configuration.
 5. The device of claim 1,wherein the connector is flexible and has a flexural rigidity of lessthan about 0.75×10⁻³ kg-m² /rad.
 6. The device of claim 1, wherein theconnector is flexible and has a flexural rigidity of less than about0.45×10⁻³ kg-m² /rad.
 7. The device of claim 1, wherein at least one ofthe regions comprises an electronic assembly electrically connected tothe power source.
 8. The device of claim 1, wherein at least one of theregions consists essentially of an electrode assembly.
 9. The device ofclaim 1, wherein each of the regions comprises an electrode assembly.10. The device of claim 1, wherein the connector permits angularmovement of one region relative to another region.
 11. The device ofclaim 10, wherein the connector permits the regions to deviate fromsubstantial planarity by at least about 15 degrees.
 12. The device ofclaim 1, wherein the connector permits adjustable positioning of oneregion on the body surface relative to the positioning of another regionon the body surface.
 13. The device of claim 1, wherein the connectorincludes an electrical conductor which electrically connects one of theregions to an electrical component in another region.
 14. The device ofclaim 13, wherein the electrical conductor electrically connects anelectrode assembly to an electronic controller.
 15. The device of claim13, wherein the electrical conductor comprises an electricallyconductive trace.
 16. The device of claim 15, wherein the trace iscomprised of an electrically conductive ink.
 17. The device of claim 1,wherein the connector is comprised of a substrate having an electricallyconductive ink trace.
 18. The device of claim 17, wherein the substratecomprises a multi-laminate including a layer of foam and anink-printable polyester sheet.
 19. The device of claim 1, wherein thereservoir contains a locally acting agent.
 20. The device of claim 1,wherein the reservoir contains an agent selected from the groupconsisting of local anesthetics, anti-inflammatory agents, anti-fungalagents, wart-removing agents, anti-tumor agents, anti-spasmodic agentsand erection-inducing agents.